Stabilization of esters of nitromalonic acid



' those users whoare not ?atented Feb. 6, 1951 I UNITED. STATE amuseSTABILIZATION or ESTEBS 0F NITaoMALowIc son).

Douglas A.

mazoo, Mich.,

Lyttle and David I. Weisblat, Kalaassignors to The Upjohn Company,Kalamazoo, Mich}, a. corporation of Michigan No- Drawing. ApplicationApril so, 1948.,

'12 Claims.. (0!. 260. 485) L This invention relates to a method for thestabilization of esters of nitromalonic acid and to stable compositionsproduced thereby.

Esters of nitromalonic acid have been found to be of great value in thepreparation of amino acids as isdisclosed in our copending applicationSerial 777,584, fiiedOctober 24, 1947; now Patent No. 2,528,928. Forexample,-tryptophane may be prepared. from an ester of nitromalonic acidby the followingseries of reactions:

Gramine-l-nitromalonate alpha (3- methylindole) alpha nitro malonate-ealpha nitro beta (3-indole) -propionatea1pha-amino-beta-(3-indole)-propionate alpha amino beta-(3 ind01e)-propionic acid.(tryptophane) The preparation of certain esters of nitromal onic acidhas been described (J. Chem Soc. 1935, 1). Others are disclosed in ourcopending application to which reference has been made.

When prepared and purified by the procedures therein reported, theresulting esteralways contains, as an impurity; varying quantitiesoioxides oi. nitrogen. Vigorous washing with water in acid solution,treatment. with alkali,-and distillation are necessary to remove theseoxides; The ester when so purified is suitable for use in the synthesisas outlined above.-

However, if an. ester of; is. free from oxides of nitrogen and thereforesuitable for use in syntheses is allowed to stand, either in a closedcontainer oropen to the atmosphere, for any considerable period of time,e. g., ten to thirty days. after purification, oxidesof nitrogenresulting from. the decomposition of the ester accumulate to such anextent that the ester becomes unsuited for use withoutfurtherpur-ification Thisaccmu-lation ofoxides oi nitro gen takes placeregardless of which once! the methods known to the art for thepurification of an ester of nitromalonic acid is used for the firstpurification thereof. The oxides of nitrogen resulting from thisdecomposition of an ester of nitromalo'nic acid. act as a.cata1yst forfurther decomposition, so that the accumulation of oxides of nitrogenproceeds at a progressively in:- creasing rate This precludes theirstorage and shipmentiawfay' from the point 01 manufacture to users whoare. at some distance irom the site of manu acture, which in turnseriously attests the availability or est'e'rsof; nitromalo'nic acid. toequ pped for its immediate preparatiqn. The

expense. or he, estersby requirin we-Ma s e ces nitromalonic acid whichIt. is, an object of this invention to provide-a :inethod for preventingthe iormation of oxides of nitrogen in esters of nitromalonic acid. Itis an additional object of the-invention-to provide egg-method for theremoval of oxidesof nitrogen from esters of nitromaionic acid. It is afurther object of this invention to stabilize esters of nitromalonicacid so that they may be stored for considerable periods of time atordinary temperature without decomposition. Other objects of theinvention will become apparent herein-- after.

The obiects, of this invention may be accomplished readily and. rapidlyby treating the ester ofjnitromalonicacid, which is desired to bestasbilized with an acid amide. The term "stabilize" asj herein used,means to prevent such decomposition of an ester of nitromalonic acid wich. gives' oxides of nitrogen as one product of the. decomposition.-

' The, method of the present invention may be carried out at any timeduring orafter the-i501 lation' of the ester, as soon as most. of the excess of nitric acid used for nitration, when nitra-- tion is employedinthe previous step, has been removed. The stabilization may beaccomplished in a. number of ways. For example, the ester ofnitrbmaloxiicacid, after-removal of i.- tric'acid, may be thoroughlymixed with an aqueous solution ofthe acid amide stabilizing agent.- Ihismixing oI-the ester,. or a water-immisciblesolvent solution of the.ester, with the acid amide may be done at any desired point inpurification procedures knownto the art, but preferably 8-1 lessdetrimental for amoun usually least once before distillation of theproduct. The treatment may he carried outjonce or several times duringthe various purification steps' as desired, When the, treatment of thisinvention of distillation maybe o Ir-iitted as the product obtained issuitable Ior some chemical syntheses without distillation. A l afterpurification by known methods may be treated by the direct additionj"oianiamlde. The quantity of the amiderequired' ternatively, the ester,

d is small, usually less than five per-E to-be-add.

nitromalonate, and! unat b :we eht of he.

any exces s present need notbe removed. The I left .in admhrturewlththenitroq malonatejtorbest results and most effective stas 'biliaationiless than about one percent byweight.

la k of stabil ty further.

of the nitromalonate. In any event, 'wa'shing' is ontinued until theoxides. are completely rewoven a eyideneed by a n ativ rpowewec'ae a theintended subsequent use.-

of this invention results only from initial com-' plete removal of theoxides, or whether the small amount of the amide stabilizing agent whichis not removed during washing operations removes the oxides as rapidlyas they are formed, thus preventing their autocatalytic street, is notpresently known. The invention is, however, not limited by the abovepossible explanation of a mechanism by which the stabilization isaccomplished, as it is of importance only that stabilization doesresult.

Any selected acid amide may be used as stabilizing agent, whetherunsubstituted or substituted on the amide nitrogen by a single alkyl,aryl, alkaryl or similar group. Such are primary or secondary, but nottertiary. amides.

Representative amides which may be used in the process of this inventionare acetamide, pro pionamide, oxamide, succinamide, benzamide, urea, anN-monoalkylurea, malonamide, and others. Mono-substituted amidescorresponding to the above unsubstituted amides are also suitable.Water-soluble amides are preferred in certain modifications of themethod of this invention. As far as the nitromalonic ester is concerned,this may be, for example, the dimethyl, diethyl, dipropyl. dibenzyl,diisopropyl, monoethylmonopropyl or other ester of nitromalonic acid, ora substituted nitromalonic ester, such as alphaalkyLaipha-aralkyl, oralpha-(3-methylindole)- malonic acid and the like.

A preferred procedure for the stabilization of an ester of nitromalonicacid is as follows: The ester, or a solution of the ester in an inertwater immiscible solvent such as chloroform, ether, or benzene, isthoroughly mixed with a dilute aqueous or other solution of the amide,preferably urea or acetamide. The mixture is then allowed to stand untiltwo distinct layers are formed. The ester layer is separated, solventremoved, and the ester of nitromalonic acid distilled if desired. Shouldthe ester be distilled, it is preferable either to repeat the mixingwith the amide or to dissolve a small quantity of amide in the ester.When it is not necessary for the nitromalonic acid ester to besubstantially colorless, the distillation step may be omitted.- Othermodifications of the method of mixing the amide and ester ofnitromalonic acid within the skill. of the art may be used and will befound satisfactory.

The following examples are illustrative of the invention but are not tobe construed as limiting.

Example 1 To nine hundred grams of diethyl malonate, cooled to zerodegrees centigrade and protected fromatmospheric moisture, there wasadded with stirring ,2200 milliliters of fuming nitric acid tsp. gr.1.5) over a period of .two and one-quarter hours. The temperature of thereaction mixture was maintained at zero degrees 'centigrade foranadditional half hour, allowed to warm to 30 degrees centigrade duringan hour, and then cooled to zero for an additional two and onequarterhours. The cold reaqtion..,mixture was poured into three gallons of iceand water. The

4 crude diethyl nitromalonate was extracted with three separate portionsof chloroform and the chloroform extract washed twice with cold water.The nitro ester was extracted from the chloroform with ten' percentsodium carbonate, and the resulting water solution of the sodium salt ofdiethyl nitromalonate extracted twice with "three-liter portions ofchloroform. The aqueous solution was cooled with ice and acidified bythe slow addition of hydrochloric acid. Three extractions, using twoliters of chloroform for each extraction, separated the diethylnitromalonate from the water solution. The chloroform solution was driedover anhydrous magnesium sulfate, chloroform removed, and the residuefractionally distilled. There was thus obtained 893.4 grams of diethylnitromalonate distilling at 78-80 degrees centigrade at a pressure of0.35 millimeter of mercury.

The product still contained oxides of nitrogen as shown by its odor andgreenish color. Starchpotassium iodide paper gave a purple color when adrop of the product was placed on the moist paper.

Example 2 Ten grams of the product from Example 1" was placed in a testtube and allowed to stand. exposed to the air at room temperature. Atthe.

P end of 30 days, the accumulation of oxides of nitrogen was so greatthat an attempted sythesis of tryptophane using this material was notentirely successful from several standpoints.

Example 3 Ten grams of diethyl nitromalonate from Example 1 wasdissolved in an equal quantity of r 4 benzene. The benzene solution wasshaken with about 5 milliliters of one percent solution of urea inwater. -The water layer was separated, the benzene solution dried, andbenzene removed. The residual diethyl nitromalonate was free ofoxides ofnitrogen as shown by a negative starchpotassium iodide test. The esterwas unchanged after three months standing in an open test tube; and thestarch-potassium iodide test for oxidesof nitrogen was negative.

Example 5 One kilogram of diethyl malonate was nitrated, with fumingnitric acid (sp. gr. 1.5) as in Example 1. The reaction mixture wasdilutedwith 3.5 gallons of ice water and the ester extracted us ingbenzene as the solvent. The benzene solu--. tion was washed twice withwater andonce with three liters of a one-percent solution of urea inwater. After this wash, a starch-potassium iodide paper test 'of thebenzene solution was negative. The diethyl nitromalonate was extractedfrom. the benzene with 10 percent aqueous solution of sodium carbonate,the sodium carbonate solu-.. tion extracted with-benzene. and thenslowly? acidified with'hydrochloric acid. The acidified solution wasextracted with benzene, and the benzene solution washed twice with waterand once with three liters of a one-percent solution of urea in water.The benzene solution wa dried and the benzene removed. The residualdiethyl 'niltromalonate was slightly yellow but completely free ofoxides of nitrogen as shown by the ab sence of green color, odor, and anegative starchpotassium iodide paper test. After standing one month atroom temperature, no decomposition had occurred as shown by a negativestarchpotassium iodide paper test.

Example 6 test tube at room temperature. .After thirty days there was noevidence of evolution of oxides of nitrogen.

in a manner similar to that of the above examples, other esters ofnitromalonic acid may i be treated to remove oxides of nitrogen. When soremoved the esters show no signs of decomposition upon standing at roomtemperature, either in closed containers or when exposed to theatmosphere. Among specific esters.which may be so stabilized aredimethyl nitromalonate, diphenyl nitromalonate, dibenzyl nitromalonate,dihexyl nitromalonate, corresponding esters of substitutednitromalonates, and the like.

It is to be understood that this invent-ion is not to be limited to theexact methods and compositions hereinbefore described, since obviousmodifications will occur to a person skilled in the art from a study ofthe foregoing.

We claim:

1. Astabilized composition comprising an ester of nitromalonic acid, anda quantity of an acid amide selected from the group consisting ofprimary and secondary carboxylic acid amides sufflcient to stabilizesaid ester of nitromalonic acid against decomposition to oxides ofnitrogen.

2. A stabilized composition comprising an ester of nitromalonic acid anda quantity of. an acid amide selected from the group consisting ofprimary and secondary carboxylic acid amides sufficient to stabilizesaid ester of nitromalonic acid against decomposition to oxides ofnitrogen, said composition giving a negative test to starch-potassiumiodide paper. y

3. A stabilized composition comprising a dialkyl.

ester of nitromalonic acid and a sufiicient quantity of an amideselected from the group consisting of primary and secondary carboxylicacid amides to stabilize said dialkyl nitromalonate againstdecomposition to oxides of nitrogen.

4. A stabilized composition comprising a diethyl' nitromalonate and asuflicient quantity of an amide selected from the group consisting ofprimary and secondary'oarboxylic acid amides to stabilize said diethylnitromalonate against decomposition to oxides of nitrogen.

5. A stabilized composition comprising diethyl nitromalonate and asufiicient quantity of an amide selected from the group consisting ofprimary and secondary carboxylic acid amides to stabilize said diethylnitromalonate against decomposition to-oxides of nitrogen, saidcomposition giving a negative test to starch-potassium iodide paper.

6. A product as in claim 5 wherein the amide is acetamide.

7. A product as in claim 5 wherein the amide is urea.

8. The process comprising mixing an ester of nitromalonic acid with asolution of an acid amide selected from the group consisting of primaryand secondary carboxylic acid amides and separating products resultingfrom the mixture includin a stabilized nitromalonate.

'9. The process including the step of mixing a nitromalonic acid esterwith an aqueous solution of an amide selected from the group consistingof primary and secondary carboxylic acid amides and recovering thestabilized nitromalonic ester.

10. The process comprising mixing a waterimmiscible solvent solution ofan alkyl nitromalonate with an aqueous solution of an amide selectedfrom the group consisting of primary and secondary carboxylic acidamides and recovering the stabilized nitromalonic acid ester.

11. A proces comprising mixing a benzene solution of diethylnitromalonate and a water solution of urea, separating the solutions,and recovering stabilized diethyl nitromalonate.-

12. A method for the stabilization of esters of nitromalonic acidincluding mixing therewith of a soluton of an acid amide selected fromthe group consisting of primary and secondary carboxylic acid amides andremoving the amide, the amount of amide added bein suificient toaccomplish substantially complete removal of dissolved .oxides ofnitrogen therefrom so that a starchpotassium iodide test paper will givea negative test when placed in contact with said ester.

DOUGLAS A. LYI'TLE. DAV1ID I. WEISBLAT.

No references cited.

1. A STABILIZED COMPOSITION COMPRISING AN ESTER OF NITROMALONIC ACID ANDA QUANTITY OF AN ACID AMIDE SELECTED FROM THE GROUP CONSISTING OFPRIMARY AND SECONDARY CARBOXYLIC ACID AMIDES SUFFICIENT TO STABILIZESAID ESTER OF NITROMALONIC ACID AGAINST DECOMPOSITION TO OXIDES OFNITROGEN